Dyslipidemia refers to a condition (or a group of conditions) wherein a patient has an abnormal amount of lipids in the blood. Most dyslipidemias are hyperlipidemias, including hypercholesterolemia, hyperglyceridemia, hyperlipoproteinemia and combined hyperlipidemia. Dyslipidemia may be manifested by an increase in the levels of total cholesterol, the low-density lipoprotein (LDL) cholesterol, the triglyceride concentrations, and a decrease in the high-density lipoprotein (HDL) cholesterol concentration in the blood.
Dyslipidemia is also one of the main risk factor for the development of diabetes. It has been shown to modulate β-cell function and survival. The influence of dyslipidemia on the β-cells of diabetic patients depends on a patient's specific lipid profile. Free fatty acids and lipoproteins have been shown to be pro-apoptotic for the β-cell. Lipoproteins may also similarly affect β-cell survival and function, whereby very-low-density lipoprotein (VLDL) and LDL are pro-apoptotic, while HDL is protective.
Dyslipidemia is also one of the major risk factors for cardiovascular disease in diabetes mellitus. In diabetic patients, 13% of men and 24% of women had increased total plasma cholesterol levels, 19% of men and 17% of women had increased plasma triglyceride levels, 9% of men and 15% of women had increased plasma LDL cholesterol levels, and 21% of men and 25% of women had decreased plasma HDL cholesterol levels. High levels of total cholesterol, LDL cholesterol and triglyceride were defined as values above the corresponding 90th percentile for the US population. The similar pattern of altered plasma lipid profiles is also observed in UK.
For adults with diabetes, it has been recommended that the levels of total cholesterol levels are less than 200 mg/dL (5.0 mmol/L), and that the levels of LDL, HDL, total cholesterol and triglyceride be measured every year. Optimal LDL cholesterol levels for adults with diabetes are less than 100 mg/dL (2.60 mmol/L), optimal HDL cholesterol levels are equal to or greater than 40 mg/dl (1.0 mmol/l) in men and 50 mg/dL (1.02 mmol/L) in women, and desirable triglyceride levels are less than 150 mg/dL (1.7 mmol/L).
For most patients, the dyslipidemia therapy commonly includes 1) lifestyle and nutrition intervention; 2) hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, such as atorvastatin, cerivastatin, fuvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin; 3) niacin and derivatives, such as niceritrol, nicofuranose, aluminum nicotinate, nicotinyl alcohol and acipimox; 4) fibrates such as bezafibrate, aluminum clofibrate, gemfibrozil, fenofibrate, simfibrate, ronifibrate, ciprofibrate, etofibrate, clofibride and clinofibrate; 5) cholesterol absorption inhibitors, such as ezetimibe; 6) bile acid sequestrants, such as cholestyramine, colestipol, colestilan, colextran and colesevelam; 7) omega-3 fatty acid; and 8) cholesterylester transfer protein (CETP) inhibitors, such as anacetrapib, dalcetrapib and torcetrapib.
Interleukin-1β (IL-1β) is a pro-inflammatory cytokine associated with dyslipidemia and diabetes. Elevated levels of IL-1β in chronic dyslipidemia result in secretion of chemokines and other cytokines, increased expression of adhesion molecules, activation of endothelial and smooth muscle cell proliferation, macrophage activation, and increased vascular permeability.
IL-1β also inhibits β-cell function and promotes Fas-triggered apoptosis, in part by activating the transcription factor nuclear factor-κB (NF-κB). In vitro exposure of islets from nondiabetic organ donors to high glucose levels results in increased production and release of IL-1β, followed by NE-κB activation, Fas upregulation, DNA fragmentation, and impaired β-cell secretory function. The IL-1 receptor antagonist protects cultured human islets from these deleterious effects. β-Cells themselves were identified as the islet cellular source of glucose-induced IL-1β. In vivo, IL-1β-producing β-cells were observed in pancreatic sections of type 2 diabetic patients, but not in healthy subjects. These findings implicate an inflammatory process in the pathogenesis of glucotoxicity in type 2 diabetes and identify the IL-1β pathway as a target to preserve β-cell mass and function in this condition.
IL-1β modulators, such as IL-1 receptor antagonists, IL-1 Traps, human IL-1β monoclonal antibodys and IL-1β inhibitors, were previously shown to be useful for the treatment or prophylaxis of type 2 diabetes. However, no literature has reported that IL-1β modulators can improve the glycosylated hemoglobin (HbA1c) control in patients with dyslipidemia.